MACROPHAGE-DEPENDENT REGULATION OF AXONAL REGENERATION FOLLOWING NEONATAL SCIATIC NERVE INJURY

Peripheral nerve injuries in adult mammals are commonly followed by effective axonal regeneration, whereas comparable lesions sustained during early postnatal development lead to limited regrowth and substantial motoneuron loss. The cellular mechanisms responsible for this age-dependent difference remain poorly defined. We employed a rat neonatal sciatic nerve regeneration/degeneration model to examine how the maturity of the injured nerve environment influences regenerative outcome. Sciatic nerve segments obtained from older neonatal donors (P6) were transplanted into younger recipients (P3) and regenerative responses were assessed using single-cell RNA sequencing (scRNA-seq) and immunohistochemical analysis. A significant enhancement in axonal regrowth was observed in animals that received grafts from postnatal day 6 donors in comparison to grafts derived from younger animals (P3). This effect was accompanied by distinct differences in the onset, persistence and composition of the macrophage response at the injury site. scRNA-seq analysis of the cells identified as fibroblasts and immune cells revealed the most promising mechanisms that potentially control the regeneration process. Candidate genes associated with axon regeneration are predominantly linked with immune response pathways and the organisation of the extracellular matrix. In this study, we demonstrate a significant diversity in cells that contribute to the formation of the injured sciatic nerve microenvironment, thereby influencing the process of nerve regeneration. This may facilitate understanding of the mechanisms regulating differentiation and subsequent de- and re-differentiation of cells in response to nerve injury, thereby supporting the restoration of functions lost through injury in the mammalian peripheral nervous system.
Research funded by NCN (2020/37/B/NZ4/04065)